HbA1c

HbA1c is the fraction of haemoglobin that has glucose bound irreversibly to the N-terminal valine of the beta chain. Glycation is proportional to ambient glucose over the life of the red cell. The result reflects mean glucose over the previous 8 to 12 weeks, with about half of the signal from the last month. It is measured by ion exchange HPLC, immunoassay, enzymatic methods, capillary electrophoresis or boronate affinity, and needs no fasting.

It is used to diagnose diabetes and prediabetes, and is the main measure of long term glycaemic control. It correlates with the risk of microvascular complications. It does not show glucose variability, hypoglycaemia or recent change, and it is unreliable whenever red cell turnover or haemoglobin structure is abnormal.

Indications. Diagnosis and screening of diabetes and prediabetes in asymptomatic adults at risk, monitoring of treatment every 3 months until stable and every 6 months thereafter, assessment after a change in therapy, and assessment of glycaemic control in pregnancy with pre-existing diabetes (with other measures).

Specimen. EDTA whole blood, stable for about 1 week at 2 to 8 °C. Capillary point-of-care devices are used for monitoring, and for diagnosis only when the device is certified for it.

Units and conversion. Results are given in mmol/mol and in the older % units. Percentage equals 0.0915 times the mmol/mol value plus 2.15. Estimated average glucose in mmol/L is about 1.59 times the % value minus 2.59 (in mg/dL, 28.7 times the % value minus 46.7).

Diagnosis.

• Normal: under 39 mmol/mol (5.7%) in one scheme, and under 42 mmol/mol (6.0%) in another.
• Prediabetes: 39 to 47 mmol/mol (5.7 to 6.4%), or 42 to 47 mmol/mol (6.0 to 6.4%) in the second scheme.
• Diabetes: 48 mmol/mol (6.5%) or more.
• A single value in the diabetic range is confirmed on a repeat sample unless the patient is symptomatic with a diagnostic glucose. Two different tests over their thresholds on the same sample confirm the diagnosis. If two tests disagree, repeat the abnormal one.
• A value under 48 mmol/mol does not exclude diabetes, and fasting glucose or the glucose tolerance test remains necessary when symptoms or risk persist.

Where HbA1c is not used for diagnosis. Suspected type 1 diabetes with rapid onset, symptoms of less than 2 months, pregnancy, children with suspected type 1 diabetes, pancreatic disease, cystic fibrosis, recent or high dose corticosteroids, anaemia or conditions altering red cell survival, haemoglobin variants where the assay is affected, and dialysis.

Targets in diagnosed diabetes (individualised).

• Most adults: 53 mmol/mol (7.0%) or less.
• Newly diagnosed, treated by lifestyle or metformin, low hypoglycaemia risk: 48 mmol/mol (6.5%) or less.
• Treated with sulphonylureas or insulin: about 53 mmol/mol (7.0%), accepting 58 mmol/mol (7.5%) if hypoglycaemia is a risk.
• Frailty, advanced complications, limited life expectancy or hypoglycaemia unawareness: 58 to 69 mmol/mol (7.5 to 8.5%), avoiding symptomatic hyperglycaemia.
• Children and adolescents with type 1 diabetes: 53 mmol/mol (7.0%) or less, with lower values in some services.
• Pregnancy with pre-existing diabetes: about 42 to 48 mmol/mol (6.0 to 6.5%) when this can be reached without hypoglycaemia.

Frequency. Every 3 months after a change in therapy or when targets are not met, and every 6 months when stable. A change of about 5 mmol/mol (0.5 percentage points) is a usual clinically significant difference.

Falsely low results (shortened red cell survival or reduced glycation).

• Haemolysis and haemolytic anaemias, hypersplenism, recent blood loss, recent transfusion, and sickle cell disease.
• Rapid reticulocytosis during treatment of iron, B12 or folate deficiency.
• Pregnancy (second and third trimesters), chronic kidney disease treated with erythropoiesis stimulating agents, dapsone, ribavirin and some antiretroviral drugs.
• Raised foetal haemoglobin in some assays.

Falsely high results.

• Iron deficiency, vitamin B12 and folate deficiency (reduced erythropoiesis with older red cells).
• Splenectomy and asplenia.
• Uraemia with carbamylated haemoglobin in some methods, and, in older assays, high dose aspirin, alcohol, severe hypertriglyceridaemia and hyperbilirubinaemia.
• Some haemoglobin variants, depending on the assay.

Haemoglobin variants. HbS, HbC, HbE, HbD and elevated HbF can interfere, with the direction and size of error depending on the method. Many HPLC and capillary electrophoresis assays display variants and warn of them. Boronate affinity and some enzymatic methods are less affected by common variants. A variant that shortens red cell survival (HbSS, HbSC) makes any HbA1c unreliable, and fructosamine, glycated albumin, continuous glucose monitoring or glucose based tests are used.

Ancestry. HbA1c is on average about 3 to 4 mmol/mol (0.3 to 0.4 percentage points) higher in people of African ancestry than in people of European ancestry at the same mean glucose, partly from sickle trait and glycation differences. This does not change the thresholds, but supports using glucose tests when the picture is unclear.

Other limits. It lags behind rapid change in glucose, and it hides marked variability and hypoglycaemia. Point-of-care devices have wider imprecision.

Critical values and findings needing immediate action. A value of 86 mmol/mol (10%) or more with weight loss, polyuria, vomiting, abdominal pain or drowsiness needs a same day glucose and ketone measurement. A very low value in a treated patient with symptoms needs a search for hypoglycaemia or red cell disorder.

Special groups.

• Pregnancy: HbA1c falls and is not used to diagnose gestational diabetes. It is used at booking to detect pre-existing diabetes.
• Children: type 1 diabetes can present with a normal or mildly raised value in rapid onset disease.
• Older adults: values rise modestly with age, and anaemia is common.
• Regions with high rates of iron deficiency, haemoglobinopathy or malaria: glucose based tests are more reliable.
• Chronic kidney disease: results are unreliable in advanced disease, so combine them with glucose monitoring.

Follow up tests. Fasting plasma glucose, oral glucose tolerance test, full blood count, ferritin, haemoglobin electrophoresis or HPLC, fructosamine, urine albumin-to-creatinine ratio, lipid profile, retinal screening, continuous glucose monitoring, islet autoantibodies and C-peptide when type 1 diabetes is suspected.